Process for making CGRP receptor antagonists

Abstract

The invention encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine, utilizing a highly effective spiroacid synthesis.

What is claimed is: 
     
       1. A process for making a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is selected from —C(R 3 )═, wherein R 3  is hydrogen, F or CN; 
         Y is N; 
         R 1  is selected from the group consisting of: C 1-4 alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more F substituents as allowed by valence; and 
         R 2  is selected from hydrogen, methyl, F, Cl, or Br; 
         comprising initiating the reaction of a compound of Formula F 
       
       
         
           
           
               
               
           
         
         wherein 
         E 1  is selected from halogen, —C(O)—O—R″, —CN, —CONRR′, —NRR′, —CH 2 —OR, OR, methyl and vinyl, wherein each R and R′ are independently H, C 1-6 alkyl, aryl, heteroaryl or benzyl and R″ is H or a carbon containing substituent capable of being solubilized to a carboxylic acid, 
         E 2  is a functional group that has leaving ability, and 
         PG is a nitrogen protecting group, 
         in an organic phase, in the presence of a bis-quaterary cinchona alkaloid salt and an inorganic base in an aqueous phase, to form a biphasic medium comprising the aqueous phase and organic phase, to make a compound of Formula G 
       
       
         
           
           
               
               
           
         
         when E 1  is other than —C(O)—O—H, replacing E 1  with or converting E 1  to a carboxylic acid utilizing a suitable chemical reaction to yield a compound of Formula H 
       
       
         
           
           
               
               
           
         
         deprotecting the compound of Formula H to yield the compound of Formula C 
       
       
         
           
           
               
               
           
         
         optionally isolated as a salt, and coupling the compound of Formula C with a compound of Formula B 
       
       
         
           
           
               
               
           
         
         optionally as a salt, under conditions for an amide bond formation between an acid and an amine to yield a compound of Formula I. 
       
     
     
       2. The process according to  claim 1  wherein the bis-quaternary cinchona alkaloid salt has the chemical structure of Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R A  is 
       
       
         
           
           
               
               
           
         
         R B  is selected from hydrogen and methoxy, 
         R C  and R D  are independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, aryl-C 1-4 alkyl and heteroary-C 1-4 alkyl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl and the aryl and heteroaryl portions of aryl-C 1-4 alkyl and heteroary-C 1-4 alkyl are optionally substituted with one to five substituents independently selected from R F , 
         R E  is selected from the group consisting of hydrogen, C(O)R, C(O)OR, CONRR′, and C 1-6 alkyl, 
         R F  is selected from the group consisting of C 1-4 alkyl, aryl, C 1-4 alkoxy, hydroxy, CN, CO 2 R, CONRR′, SR, SO 2 R, SO 3 R, PR 3 , PO(OR) 2 , PO(OR)(NRR′), PO(NRR′) 2 , P(OR) 2 , P(OR)(NRR′), P(NRR′) 2 , SiRR′R″, B(OR) 2 , C(O)R, NRR′, NO 2 , halogen and CF 3 , 
         each R, R′ and R″ is independently selected from the group consisting of, H, C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, aryl, heteroaryl, —CH 2 -aryl, —CH 2 -heteroaryl, and 
         each X and Y are independently anions selected from halide, OH, HSO 4 , SO 4 , BF 4 , SbF 6 , carboxylate, carbonate, hydrogencarbonate, NO 3 , sulfonate, hexafluorophosphate, phosphate, hydrogen phosphate and perchlorate. 
       
     
     
       3. The process according to  claim 1  wherein E 1  is halogen and carbonylation of the compound of Formula G is via palladium catalyzed reaction with carbon monoxide whereby the compound of Formula G is reacted with carbon monoxide in the presence of a palladium catalyst, a first base and a ligand to yield a compound of Formula H. 
     
     
       4. The process according to  claim 3  wherein the ligand is a phosphine ligand. 
     
     
       5. The process according to  claim 1  wherein E 1  is halogen and carbonylation of the compound of Formula G is via Grignard reagent formation whereby the compound of Formula G is reacted with magnesium or lithium followed by CO 2  and an acid to yield a compound of Formula H. 
     
     
       6. The process according to  claim 1  wherein PG is selected from the group consisting of: C 1-6  alkyl, vinyl, C(O)—O-L, C(O)-L, aryl, hetroaryl, benzyl, benzhydryl, trityl, anthranyl and C 1-6 alkoxymethyl, wherein aryl, heteroaryl, benzyl, benzyhydryl and trityl optionally are substituted with 1 to 3 substituents independently selected from methoxy and nitro, C 1-6 alkoxymethyl is optionally substituted with trimethylsilyl and L is C 1-6 alkyl, aryl or benzyl. 
     
     
       7. The process according to  claim 1  wherein E 2  is selected from the group consisting of: halogen, OMs, OTs, OBs, OP(O)(OR i ) 4 , OC(O)R i , OC(O)OR i  and OC(O)NR i R ii , wherein R i  and R ii  are independently selected from H and C 1-6 alkyl. 
     
     
       8. The process according to  claim 1  wherein the organic phase is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, ethyl ether, isopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, isopropyl acetate, ethyl acetate, hexane, heptane, cyclohexane, dichloromethane, dichloroethane, acetonitrile, acetone, methyl ethyl ketone, butanol and amyl alcohol. 
     
     
       9. The process according to  claim 1  wherein the inorganic base is selected from the group consisting of: sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, cesium hydroxide, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium phosphate and potassium phosphate. 
     
     
       10. The process according to  claim 1  wherein the organic phase is toluene and the inorganic base is sodium hydroxide. 
     
     
       11. The process according to  claim 1  wherein the compound of Formula C is isolated as a salt selected from HCl, H 2 SO 4 , Na, K, Li, H 3 PO 4  and HBF 4 . 
     
     
       12. The process according to  claim 2  wherein, in the bis-quaternary cinchona alkaloid salt of Formula II, R C  and R D  are independently C 1-6 alkyl or benzyl and wherein the C 1-6 alkyl or phenyl portion of each of said benzyl is optionally substituted with one to five substituents independently selected from R F . 
     
     
       13. The process according to  claim 12  wherein in the bis-quaternary cinchona alkaloid salt of Formula II, R B  is methoxy. 
     
     
       14. The process according to  claim 13  wherein in the bis-quaternary cinchona alkaloid salt of Formula II, R F  is selected from halogen and methoxy. 
     
     
       15. The process according to  claim 1  wherein the bis-quaternary cinchona alkaloid salt is of the formula 
       
         
           
                 
               
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                 
                 
                 
                 
                 
               
                   R B   
                   R C   
                   R D   
                   X −   
                   Y −   
                 
                     
                 
                   OMe 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Br 
                   Br 
                 
                     
                 
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Br 
                   Br 
                 
                     
                 
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   I 
                   I 
                 
                     
                 
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Br 
                   I 
                 
                     
                 
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Br 
                   Br 
                 
                     
                 
                   H 
                   Me 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Br 
                   I 
                 
                     
                 
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Br 
                   Br 
                 
                     
                 
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Allyl 
                   Br 
                   Br. 
                 
                     
                 
             
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       16. The process according to  claim 1  further comprising making a compound of Formula F by reacting a compound of Formula J 
       
         
           
           
               
               
           
         
         wherein E 3  and E 4  are independently functional groups that have leaving ability, 
         with R 4 —Z 1  or a salt thereof and HC(O)—N(R 5 ) 2  wherein R 4  is C 1-6 alkyl, Z 1  is magnesium halide or lithium and each R 5  is independently H or C 1-6 alkyl, to yield a compound of Formula K 
       
       
         
           
           
               
               
           
         
         reacting the compound of Formula K with a first reducing agent to yield a compound of Formula L, wherein said first reducing agent is independently: H 2 , HCO 2 H, HCO 2 NH 4 , NaBH 4 , LiBH 4  or LiAlH 4 : 
       
       
         
           
           
               
               
           
         
         introducing an alcohol protecting group (APG) to the compound of Formula L to yield a compound of Formula M, wherein APG is: THP, tetrahydrofuryl, SEM, MOM, BOM, TMS, TES, TBDMS, TIPS or benzyl which is optionally substituted with 1 to 3 substituents independently selected from halogen, methyl, methoxy and nitro: 
       
       
         
           
           
               
               
           
         
         (i) reductive carbonylation of the compound of Formula M via palladium catalyzed reaction with carbon monoxide and hydrogen or (ii) reacting the compound of Formula M with R 6 —Z 2  or a salt thereof and HC(O)—N(R 7 ) 2  wherein R 6  is C 1-6 alkyl, Z 2  is magnesium halide or lithium and each R 7  is independently H or C 1-6 alkyl, to yield a compound of Formula N 
       
       
         
           
           
               
               
           
         
         and following step (a) or step (b) below to yield a compound of Formula F 
         Step (a)—coupling the compound of Formula N with a compound of Formula O 
       
       
         
           
           
               
               
           
         
         in the presence of a second base to yield a compound of Formula P 
       
       
         
           
           
               
               
           
         
         and reacting the compound of Formula P with a second reducing agent, wherein said second reducing agent is independently: H 2 , HCO 2 H, HCO 2 NH 4 , NaBH 4 , LiBH 4  or LiAlH 4 , followed by alcohol deprotection and replacement of the alcohol with the appropriate leaving group E 2  to yield a compound of Formula F, or 
         Step (b)—reducing the aldehyde in the compound of Formula N to an alcohol to produce a compound of Formula Q 
       
       
         
           
           
               
               
           
         
         reacting the compound of Formula Q with an activating agent to yield a compound of Formula R 
       
       
         
           
           
               
               
           
         
         wherein E 5  is independently a functional group that has leaving ability, and coupling the compound of Formula R with a compound of Formula O in the presence of a second base wherein said second base is: DBU, N,N-Diisopropylethylamine, TEA, morpholine or N-methylmorpholine to yield a compound of Formula S 
       
       
         
           
           
               
               
           
         
         followed by alcohol deprotection and replacement of the alcohol with the appropriate leaving group E 2  to yield a compound of Formula F. 
       
     
     
       17. The process according to  claim 16  wherein E 3  and E 4  are independently halogen. 
     
     
       18. The process according to  claim 16  wherein the compound of Formula N is made by reacting the compound of Formula M with R 6 —Z 2  or a salt thereof and HC(O)—N(R 7 ) 2  wherein R 6  is C 1-6 alkyl, Z 2  is magnesium halide or lithium and each R 7  is independently H or C 1-6 alkyl, to yield a compound of Formula N. 
     
     
       19. The process according to  claim 16  wherein the second base is an inorganic base.